JIP-1/IB-1 is a cytosolic adaptor protein that contains multiple protein-protein interaction modules and is thought to recruit signaling molecules to transmembrane receptors. This adaptor interacts with members of the low-density lipoprotein receptor family. Of these receptors, ApoER2 performs a crucial role in brain development as a receptor for Reelin, a protein that is secreted in specific regions of the brain and guides neuronal migrations. JIP-1 binds to p190RhoGEF, a guanine nucleotide exchange factor (GEF) that is preferentially expressed in the brain and regulates the morphology of neurons by activating the small GTPase RhoA. RhoA collapses membrane extensions in differentiated neurons and prevents neural regeneration following injury in vivo. Collectively, these findings raise the possibility that by relaying Reelin-initiated signals from ApoER2 to p190RhoGEF, JIP-1 plays a role in normal brain development. Within this model, the central hypothesis of this proposal is that JIP-1 regulates neuronal differentiation and migration, and thus brain development, by controlling p190RhoGEF function. Experiments are described that will test the involvement of JIP-1 in p190RhoGEF subcellular localization, signaling capacity, and influence on differentiation and morphology. Furthermore, the importance of the JIP-l-p190RhoGEF association in brain development and neuronal migration will be investigated by disrupting this complex in mutant mice .